tbuckley/cabot-search huggingface dataset:
Estimates of SARS-CoV-2 Omicron BA.2 Subvariant Severity in New England
Authors: Zachary H. Strasser, Noah Greifer, Aboozar Hadavand, Shawn N. Murphy, Hossein Estiri
Journal: JAMA Network Open (2022)

Importance The SARS-CoV-2 Omicron subvariant, BA.2, may be less severe than previous variants; however, confounding factors make interpreting the intrinsic severity challenging. Objective To compare the adjusted risks of mortality, hospitalization, intensive care unit admission, and invasive ventilation between the BA.2 subvariant and the Omicron and Delta variants, after accounting for multiple confounders. Design, Setting, and Participants This was a retrospective cohort study that applied an entropy balancing approach. Patients in a multicenter inpatient and outpatient system in New England with COVID-19 between March 3, 2020, and June 20, 2022, were identified. Exposures Cases were assigned as being exposed to the Delta (B.1.617.2) variant, the Omicron (B.1.1.529) variant, or the Omicron BA.2 lineage subvariants. Main Outcomes and Measures The primary study outcome planned before analysis was risk of 30-day mortality. Secondary outcomes included the risks of hospitalization, invasive ventilation, and intensive care unit admissions. Results Of 102 315 confirmed COVID-19 cases (mean [SD] age, 44.2 [21.6] years; 63 482 women [62.0%]), 20 770 were labeled as Delta variants, 52 605 were labeled as the Omicron B.1.1.529 variant, and 28 940 were labeled as Omicron BA.2 subvariants. Patient cases were excluded if they occurred outside the prespecified temporal windows associated with the variants or had minimal longitudinal data in the Mass General Brigham system before COVID-19. Mortality rates were 0.7% for Delta (B.1.617.2), 0.4% for Omicron (B.1.1.529), and 0.3% for Omicron (BA.2). The adjusted odds ratio of mortality from the Delta variant compared with the Omicron BA.2 subvariants was 2.07 (95% CI, 1.04-4.10) and that of the original Omicron variant compared with the Omicron BA.2 subvariant was 2.20 (95% CI, 1.56-3.11). For all outcomes, the Omicron BA.2 subvariants were significantly less severe than that of the Omicron and Delta variants. Conclusions and Relevance In this cohort study, after having accounted for a variety of confounding factors associated with SARS-CoV-2 outcomes, the Omicron BA.2 subvariant was found to be intrinsically less severe than both the Delta and Omicron variants. With respect to these variants, the severity profile of SARS-CoV-2 appears to be diminishing after taking into account various factors including therapeutics, vaccinations, and prior infections.
Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer
Authors: Briana G. Nixon, Fengshen Kuo, LiangLiang Ji, Ming Liu, Kristelle Capistrano, Mytrang Do, Ruth A. Franklin, Xiaodi Wu, Emily R. Kansler, Raghvendra M. Srivastava, Tanaya A. Purohit, Alejandro Sanchez, Lynda Vuong, Chirag Krishna, Xinxin Wang, Herbert C. Morse III, James J. Hsieh, Timothy A. Chan, Kenneth M. Murphy, James J. Moon, A. Ari Hakimi, Ming O. Li
Journal: Immunity (2022)
Trained immunity is induced in humans after immunization with an adenoviral vector COVID-19 vaccine
Authors: Dearbhla M. Murphy, Donal J. Cox, Sarah A. Connolly, Eamon P. Breen, Aenea A.I. Brugman, James J. Phelan, Joseph Keane, Sharee A. Basdeo
Journal: Journal of Clinical Investigation (2022)

Background. Heterologous effects of vaccines are mediated by "trained immunity," whereby myeloid cells are metabolically and epigenetically reprogrammed, resulting in heightened responses to subsequent insults. Adenovirus vaccine vector has been reported to induce trained immunity in mice. Therefore, we sought to determine whether the ChAdOx1 nCoV-19 vaccine (AZD1222), which uses an adenoviral vector, could induce trained immunity in vivo in humans.
A FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas
Authors: Ja-Young Jang, Inah Hwang, Heng Pan, Jun Yao, Lapo Alinari, Eddie Imada, Claudio Zanettini, Michael J. Kluk, Yizhe Wang, Yunkyoung Lee, Hua V. Lin, Xiangao Huang, Maurizio Di Liberto, Zhengming Chen, Karla V. Ballman, Lewis C. Cantley, Luigi Marchionni, Giorgio Inghirami, Olivier Elemento, Robert A. Baiocchi, Selina Chen-Kiang, Sandro Belvedere, Hongwu Zheng, Jihye Paik
Journal: Journal of Clinical Investigation (2022)

Targeting lineage-defined transcriptional dependencies has emerged as an effective therapeutic strategy in cancer treatment. Through screening for molecular vulnerabilities of mantle cell lymphoma (MCL), we identified a set of transcription factors (TFs) including FOXO1, EBF1, PAX5, and IRF4 that are essential for MCL propagation. Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) with transcriptional network reconstruction analysis revealed FOXO1 as a master regulator that acts upstream in the regulatory TF hierarchy. FOXO1 is both necessary and sufficient to drive MCL lineage commitment through supporting the lineage-specific transcription programs. We further show that FOXO1, but not its close paralog FOXO3, can reprogram myeloid leukemia cells and induce B-lineage gene expression. Finally, we demonstrate that cpd10, a small molecule identified from an enriched FOXO1 inhibitor library, induces a robust cytotoxic response in MCL cells in vitro and suppresses MCL progression in vivo. Our findings establish FOXO1 inhibition as a therapeutic strategy targeting lineage-driven transcriptional addiction in MCL.
Pharmacological conversion of gut epithelial cells into insulin-producing cells lowers glycemia in diabetic animals
Authors: Wen Du, Junqiang Wang, Taiyi Kuo, Liheng Wang, Wendy M. McKimpson, Jinsook Son, Hitoshi Watanabe, Takumi Kitamoto, Yunkyoung Lee, Remi J. Creusot, Lloyd E. Ratner, Kasi McCune, Ya-Wen Chen, Brendan H. Grubbs, Matthew E. Thornton, Jason Fan, Nishat Sultana, Bryan S. Diaz, Iyshwarya Balasubramanian, Nan Gao, Sandro Belvedere, Domenico Accili
Journal: Journal of Clinical Investigation (2022)

As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic β cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by forkhead box O1 (FoxO1) ablation, but their numbers are limited. In this study, we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-β that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes.
Human NK cells confer protection against HIV-1 infection in humanized mice
Authors: Can M. Sungur, Qiankun Wang, Ayşe N. Ozantürk, Hongbo Gao, Aaron J. Schmitz, Marina Cella, Wayne M. Yokoyama, Liang Shan
Journal: Journal of Clinical Investigation (2022)

The role of NK cells against HIV-1 infections remains to be elucidated in vivo. While humanized mouse models potentially could be used to directly evaluate human NK cell responses during HIV-1 infection, improved functional development of human NK cells in these hosts is needed. Here, we report the humanized MISTRG-6-15 mouse model, in which NK cells were quick to expand and exhibit degranulation, cytotoxicity, and proinflammatory cytokine production in nonlymphoid organs upon HIV-1 infection but had reduced functionality in lymphoid organs. Although HIV-1 infection induced functional impairment of NK cells, antiretroviral therapy reinvigorated NK cells in response to HIV-1 rebound after analytic treatment interruption. Moreover, a broadly neutralizing antibody, PGT121, enhanced NK cell function in vivo, consistent with antibody-dependent cellular cytotoxicity. Monoclonal antibody depletion of NK cells resulted in higher viral loads in multiple nonlymphoid organs. Overall, our results in humanized MISTRG-6-15 mice demonstrated that NK cells provided direct anti–HIV-1 responses in vivo but were limited in their responses in lymphoid organs.
3D imaging analysis on an organoid-based platform guides personalized treatment in pancreatic ductal adenocarcinoma
Authors: Ya’an Kang, Jenying Deng, Jianhua Ling, Xinqun Li, Yi-Ju Chiang, Eugene J. Koay, Huamin Wang, Jared K. Burks, Paul J. Chiao, Mark W. Hurd, Manoop S. Bhutani, Jeffrey H. Lee, Brian R. Weston, Anirban Maitra, Naruhiko Ikoma, Ching-Wei D. Tzeng, Jeffrey E. Lee, Ronald A. DePinho, Robert A. Wolff, Shubham Pant, Florencia McAllister, Matthew H.G. Katz, Jason B. Fleming, Michael P. Kim
Journal: Journal of Clinical Investigation (2022)

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with unpredictable responses to chemotherapy. Approaches to assay patient tumors before treatment and identify effective treatment regimens based on tumor sensitivities are lacking. We developed an organoid-based platform (OBP) to visually quantify patient-derived organoid (PDO) responses to drug treatments and associated tumor-stroma modulation for personalized PDAC therapy.METHODSWe retrospectively quantified apoptotic responses and tumor-stroma cell proportions in PDOs via 3D immunofluorescence imaging through annexin A5, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK-19) levels. Simultaneously, an ex vivo organoid drug sensitivity assay (ODSA) was used to measure responses to standard-of-care regimens. Differences between ODSA results and patient tumor responses were assessed by exact McNemar's test.RESULTSImmunofluorescence signals, organoid growth curves, and Ki-67 levels were measured and authenticated through the OBP for up to 14 days. ODSA drug responses were not different from patient tumor responses, as reflected by CA19-9 reductions following neoadjuvant chemotherapy (P = 0.99). PDOs demonstrated unique apoptotic and tumor-stroma modulation profiles (P < 0.0001). α-SMA/CK-19 ratio levels of more than 1.0 were associated with improved outcomes (P = 0.0179) and longer parental patient survival by Kaplan-Meier analysis (P = 0.0046).CONCLUSIONHeterogenous apoptotic drug responses and tumor-stroma modulation are present in PDOs after standard-of-care chemotherapy. Ratios of α-SMA and CK-19 levels in PDOs are associated with patient survival, and the OBP could aid in the selection of personalized therapies to improve the efficacy of systemic therapy in patients with PDAC.FUNDINGNIH/National Cancer Institute grants (K08CA218690, P01 CA117969, R50 CA243707-01A1, U54CA224065), the Skip Viragh Foundation, the Bettie Willerson Driver Cancer Research Fund, and a Cancer Center Support Grant for the Flow Cytometry and Cellular Imaging Core Facility (P30CA16672).
Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant
Authors: Abhimanyu Garg, Wee-Teik Keng, Zhenkang Chen, Adwait Amod Sathe, Chao Xing, Pavithira Devi Kailasam, Yanqiu Shao, Nicholas P. Lesner, Claire B. Llamas, Anil K. Agarwal, Prashant Mishra
Journal: Journal of Clinical Investigation (2022)

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.
Discrete single-cell microRNA analysis for phenotyping the heterogeneity of acute myeloid leukemia
Authors: Xi Zhao, Zixun Wang, Xianglin Ji, Shuyu Bu, Peilin Fang, Yuan Wang, Mingxue Wang, Yang Yang, Wenjun Zhang, Anskar Y.H. Leung, Peng Shi
Journal: Biomaterials (2022)
Allergen-induced DNA release by the airway epithelium amplifies type 2 immunity
Authors: Yotesawee Srisomboon, Koji Iijima, Mathia Colwell, Peter J. Maniak, Marissa Macchietto, Christopher Faulk, Hirohito Kita, Scott M. O’Grady
Journal: Journal of Allergy and Clinical Immunology (2022)
Improving skin cancer management with ARTificial intelligence: A pre-post intervention trial of an artificial intelligence system used as a diagnostic aid for skin cancer management in a real-world specialist dermatology setting
Authors: Claire Felmingham, Yan Pan, Yonatan Kok, John Kelly, Douglas Gin, Jennifer Nguyen, Michelle Goh, Alex Chamberlain, Amanda Oakley, Simon Tucker, William Berry, Mark Darling, Dale Jobson, Aaron Robinson, Sara de Menezes, Charlie Wang, Anneliese Willems, Catriona McLean, William Cranwell, Nikki Adler, Miki Wada, Peter Foley, Jane Brack, Simon Cumming, Gabrielle Byars, Adrian Bowling, Zongyuan Ge, Martin Haskett, Rory Wolfe, Victoria Mar, Sarah Brennand, Christopher Chew, Sarah Chivers, Alvin Chong, Rachael Davenport, Aakriti Gupta, Emma Hiscutt, Anthony Honigman, Matthew Howard, Rebekka Jerjen, Minhee Kim, Jane Li, Wenyuan Liu, Helena Lolatgis, Zhi Mei Low, Priska McDonald, Blake Mumford, Diana Norris, Hugh Roberts, Sarah Smithson, Edmund Wee, Gwyneth Natalie Wong, Mabel Yan, Michaela Zallmann
Journal: Journal of the American Academy of Dermatology (2022)
The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2–associated multisystem inflammatory syndrome in children
Authors: Mehdi Benamar, Qian Chen, Janet Chou, Amélie M. Julé, Rafik Boudra, Paola Contini, Elena Crestani, Peggy S. Lai, Muyun Wang, Jason Fong, Shira Rockwitz, Pui Lee, Tsz Man Fion Chan, Ekin Zeynep Altun, Eda Kepenekli, Elif Karakoc-Aydiner, Ahmet Ozen, Perran Boran, Fatih Aygun, Pinar Onal, Ayse Ayzit Kilinc Sakalli, Haluk Cokugras, Metin Yusuf Gelmez, Fatma Betul Oktelik, Esin Aktas Cetin, Yuelin Zhong, Maria Lucia Taylor, Katherine Irby, Natasha B. Halasa, Elizabeth H. Mack, Sara Signa, Ignazia Prigione, Marco Gattorno, Nicola Cotugno, Donato Amodio, Raif S. Geha, Mary Beth Son, Jane Newburger, Pankaj B. Agrawal, Stefano Volpi, Paolo Palma, Ayca Kiykim, Adrienne G. Randolph, Gunnur Deniz, Safa Baris, Raffaele De Palma, Klaus Schmitz-Abe, Louis-Marie Charbonnier, Lauren A. Henderson, Talal A. Chatila
Journal: Journal of Clinical Investigation (2022)

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.
A Phase 2 Study of Palbociclib for Recurrent or Refractory Advanced Thymic Epithelial Tumors (KCSG LU17-21)
Authors: Hyun Ae Jung, Miso Kim, Hae Su Kim, Joo-Hang Kim, Yoon Hee Choi, Jinhyun Cho, Ji Hyun Park, Keon Uk Park, Bo Mi Ku, Sehhoon Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Journal: Journal of Thoracic Oncology (2022)
IL-13/IL-4 signaling contributes to fibrotic progression of the myeloproliferative neoplasms
Authors: Johanna Melo-Cardenas, Lavanya Bezavada, Jeremy Chase Crawford, Sandeep Gurbuxani, Anitria Cotton, Guolian Kang, Jeffrey Gossett, Christian Marinaccio, Rona Weinberg, Ronald Hoffman, Anna Rita Migliaccio, Yan Zheng, Marta Derecka, Ciro R. Rinaldi, John D. Crispino
Journal: Blood (2022)
Implementing computational methods in tandem with synonymous gene recoding for therapeutic development
Authors: Brian C. Lin, Nayiri M. Kaissarian, Chava Kimchi-Sarfaty
Journal: Trends in Pharmacological Sciences (2022)

Synonymous gene recoding, the substitution of synonymous variants into the genetic sequence, has been used to overcome many production limitations in therapeutic development. However, the safety and efficacy of recoded therapeutics can be difficult to evaluate because synonymous codon substitutions can result in subtle, yet impactful changes in protein features and require sensitive methods for detection. Given that computational approaches have made significant leaps in recent years, we propose that machine-learning (ML) tools may be leveraged to assess gene-recoded therapeutics and foresee an opportunity to adapt codon contexts to enhance some powerful existing tools. Here, we examine how synonymous gene recoding has been used to address challenges in therapeutic development, explain the biological mechanisms underlying its effects, and explore the application of computational platforms to improve the surveillance of functional variants in therapeutic design.
Pharmacogenomics in treatment of depression and psychosis: an update
Authors: Marin Jukic, Filip Milosavljević, Espen Molden, Magnus Ingelman-Sundberg
Journal: Trends in Pharmacological Sciences (2022)

Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.
2022 ACC Expert Consensus Decision Pathway for Integrating Atherosclerotic Cardiovascular Disease and Multimorbidity Treatment: A Framework for Pragmatic, Patient-Centered Care
Authors: Kim K. Birtcher, Larry A. Allen, Jeffrey L. Anderson, Marc P. Bonaca, Ty J. Gluckman, Aliza Hussain, Mikhail Kosiborod, Laxmi S. Mehta, Salim S. Virani
Journal: Journal of the American College of Cardiology (2022)
Engineering human spinal microphysiological systems to model opioid-induced tolerance
Authors: Hongwei Cai, Zheng Ao, Chunhui Tian, Zhuhao Wu, Connor Kaurich, Zi Chen, Mingxia Gu, Andrea G. Hohmann, Ken Mackie, Feng Guo
Journal: Bioactive Materials (2022)

pioids are commonly used for treating chronic pain. However, with continued use, they may induce tolerance and/or hyperalgesia, which limits therapeutic efficacy. The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied, in part, because current models cannot fully recapitulate human pathology. Here, we engineered novel human spinal microphysiological systems (MPSs) integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance. Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement. We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids, but also promotes their neuron maturation, neural activity, and functional development. We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia, as measured by altered neural activity, and downregulation of μ-opioid receptor expression of human spinal MPSs. The MPSs are scalable, cost-effective, easy-to-use, and compatible with commonly-used well-plates, thus allowing plug-and-play measurements of neural activity. We believe the MPSs hold a promising translational potential for studying human pain etiology, screening new treatments, and validating novel therapeutics for human pain medicine.
Table of Contents
Authors: G Bianchini, L Licata, G Viale, L Gianni, V Moreno, R Salazar, S Gruber, S Paluch-Shimon, F Cardoso, A Partridge, O Abulkhair, H Azim, G Bianchi-Micheli, M Cardoso, G Curigliano, K Gelmon, O Gentilini, N Harbeck, B Kaufman, S Kim, Q Liu, J Merschdorf, P Poortmans, G Pruneri, E Senkus, B Sirohi, T Spanic, V Sulosaari, F Peccatori, I Vaz-Luis, M Masiero, G Cavaletti, A Cervantes, R Chlebowski, E Felip, A Ferreira, P Ganz, J Hegarty, J Jeon, C Johansen, F Joly, K Jordan, B Koczwara, P Lagergren, M Lambertini, D Lenihan, H Linardou, C Loprinzi, S Rauh, K Steindorf, W Van Der Graaf, L Van De Poll-Franse, G Pentheroudakis, S Peters, G Pravettoni, J Augustin, P Soussan, A Bass
Journal: Annals of Oncology (2022)